Cancer is the 2nd leading cause after cardiovascular diseases responsible for human death. Because of the environment pollution and other factors, the incidence of malignant tumor is increasing rapidly. Based on WHO's published data of 2003, there are over 100 million patients with malignant tumor in the world. About 6.2 millions patients with malignant tumor die for cancer which accounts for 12%˜25% of the total death. It is estimated that the global new cases will reach 15 million per year in 2020. Recently, some novel anticancer drugs of protein tyrosine inhibitors have been developed and achieved great clinical benefits, however, it is still far away from meeting the growing clinical needs of cancer patients. Anticancer drug is still one of the most active areas in the worldwide drug development.
Molecular targeted cancer therapy is a strategy selectively killing tumor cells through chemical or biological approaches by interfering the key regulators of tumor cell growth. Comparing with the traditional cytotoxic drugs, molecular targeted therapy can selectively modulate key molecules which are closely related to tumor growth and treat patients with high specificity and selectivity, low toxicity and less side effects. It can also enhance the potency by combination with traditional chemotherapy and radiotherapy, and reduce the recurrence after surgery. Gleevec (STI571), the protein tyrosine kinase inhibitor, created a new era of molecular targeted therapy for cancer. The molecular targeted therapy has rapidly developed within these years. The emergence of molecular targeted therapy for cancer has impacted the traditional drug administration concepts and models. For example, because of its low toxicity and less side effects, targeted drugs usually do not reach dose-limited toxicity and maximum tolerated dose in the clinic trial phase I; satisfactory efficacy can be achieved without need for applying maximum tolerated dose for molecular targeted therapy drugs. Targeted cancer therapy is one of the hot issues and developmental tendency of cancer therapy.
Protein tyrosine kinases (PTKs) can phosphorylate the phenolic hydroxyl groups of tyrosine residues of many important proteins and further activate functions of functional proteins. There are over 520 protein kinases in human body, about half of which are protein tyrosine kinases (PTKs). These proteins play very important roles in the signal transduction pathways inside of cells and modulate a wide range of biological processes of cells including growth, differentiation, death, etc. Dysfunction of protein tyrosine kinase will cause a series of diseases. The studies show that half of protooncogenes and activation of oncogenes are related to protein tyrosine kinases. Abnormal expression of protein tyrosine kinase can cause disorder of cell proliferation regulation, and further cause tumors. In addition, abnormal expression of protein tyrosine kinase also closely relates to the tumor invasion and metastasis, the formation of new blood vessels, and resistance against chemotherapy drug. Novel protein tyrosine kinase inhibitor development has been one of the hottest issues in the world, and is also a focal point of all R&D institutions in all countries.
So far, over tens of small molecular inhibitors and antibodies of protein tyrosine kinase haven advanced into clinical trial, and some of them have been approved for clinical use and achieved excellent therapeutic effect. i.e. BCR-ABL inhibitor Gleevec for treating Philadelphia chromosome positive chronic myeloid leukemia and gastrointestinal stromal tumor; EGFR inhibitor Iressa and Tarceva for treating non-small-cell carcinoma etc. Gleevec is the first tumor drug with significant effect which was designed after knowing the pathogenesis of cancer. This drug is a milestone in molecular targeted cancer therapy. The greatness of Gleevec has been incorporated as one of the top ten science and technology news by SCIENCE magazine of USA in 2001.
Great success of the approved protein tyrosine kinase inhibitors further validates protein tyrosine kinases as promising molecular targets for clinic cancer therapy, and meanwhile validates its importance in tumor developing. Collective evidences show that protein tyrosine kinases encoded by mutant genes has direct relationship with the occurrence of tumor, such as BCR-ABL with chronic myeloid leukemia, c-Kit with GIST, SCCL and systemic mastocytosis, PDGFR with chronic myelomonocytic leukemia, dermatofibrosarcoma protuberan and hypereosinophilic syndrome, Flt3 with parts of acute granulocytic leukemia, B-Raf with melanoma, RET with thyroid carcinoma. In addition, c-KIT is also closely related to small cell lung cancer.
The first targeted therapy drug STI571 (Gleevec, Imatinib mesylate, Chinese name “Geliewei”, Novartis Pharmaceuticals), a protein tyrosine kinase inhibitor, was approved by USA FDA in 2001 for treating chronic granulocytic leukemia (CML). This drug mainly targets Bcr-Abl, cKit, PDGFR etc. In clinic, single drug treatment with STI571 can make 98% of CML patients get relieved in clinical hematology, and 53% of these get relieved in cytogenetics.
However, emerging acquired resistance has become a major challenge for clinical management of CML
With the widely application of STI571 in clinic, drug resistance has become a serious problem: part of cancer patients show primary resistance to STI571; some patients show effect at beginning of administration, but gradually show secondary resistance in the process of drug therapy. Resistance means after STI571 treatment, chronic-phase patients do not have complete hematologic response or patients at blast-phase and accelerated phase cannot recover back to chronic phase. In clinic, CML patients in blast-phase and ALL patients with positive BCR-ABL more generally develop resistance. About 70% of the two kinds of patients will develop STI571 resistance after 3˜6 month drug administration. And once the resistance happens, the situation gets worse. Resistance is considered one defense by tumor cells to avoid being killed, and has many mechanisms which include: {circle around (1)} target gene (BCR-ABL, c-KIT, PDGFR) amplification; {circle around (2)} target gene mutation; {circle around (3)} formation of the tumor clone independent of the target genes; {circle around (4)} Production of α-1 acidic glycoprotein and over-expression of multiple drug resistance gene MDR1. However, the major mechanism publically accepted is secondary mutation in the kinase domains of kinase (BCR-ABL, c-KIT, PDGFR). Studies have demonstrated that that the common point mutations closely related to resistance include E255K, E255V, T315I and D276G of BCR-ABL, and D816V of c-KIT, etc. Patients with these mutations can easily have recurrence with bad prognosis. Some reports show that only 50% of patients of metastatic gastrointestinal stromal tumor (GIST), who carry V560G mutation in c-KIT transmembrane domain, respond to STI571 and achieve good efficacy. However, another 50% of patients of metastatic gastrointestinal stromal tumor do not respond to STI571. Point mutation of c-KIT tyrosine kinase (for example D816V, T315I) shows super resistance to STI571. In vitro experiments show that STI571 cannot inhibit proliferation of cells carrying c-KIT D816V and T315I mutants; patients of systemic mastocytosis carrying D816V c-KIT do not respond to STI571.
How to overcome the resistance of STI571 is a major important topic of today's Oncological medical study. Development of new small molecule inhibitors of tyrosine kinase is an important approach to overcome the resistance of STI571. For example, small molecule tyrosine kinase inhibitors, Nilotinib (AMN107), Dasatinib (BMS-354825) which launched to market recently, show effect on part (not all) of patient carrying STI571-resistant BCR-ABL point mutations (exclude T315 mutation). Same as that STI571 does, AMN107 competitively binds to non-active type of Abl kinase. It shows stronger affinity than STI571, and is 10˜50 times more patent than STI571. AMN107 displays significant inhibition on cells harboring 15 point mutation except T315I with IC50 values in 10˜1000 nM. Different from STI571 and AMN107, BMS-354825 can bind and inhibit both the non-activated and the activated BCR-ABL. BMS-354825 displays significant inhibition on cells harboring 15 point mutation except T315I, with IC50 values ranging from 10 nM to 125 nM. However, neither AMN107 nor BMS-354825 have effect on BCR-ABL T315I mutant. AMN107 and STI571 have no effect cells have c-KIT D816V point mutation. Therefore, it is urgently needed to develop new small molecule compounds which can efficiently kill the cells with STI571-resistant c-KIT point mutation (D816V) and/or BCR-ABL point mutation (including T315I) for both academia and industry of cancer therapy in the world.
In fact, most of today's protein tyrosine kinase inhibitor antitumor drugs can induce resistance related gene mutation, and face the problems of narrow clinic application scope. Therefore, development of the second generation of protein tyrosine kinase inhibitor and improvement of the clinic effect are super meaningful.
This invention relates to compounds with formula (I). These compounds can effectively inhibit different kinds of tumor cells, and display inhibitory potency targeting Gleevec-resistant mutants both in vitro and in vivo. These inhibitors represent a new generation of protein tyrosine kinase inhibitors.